NOT FOR HUMAN CONSUMPTION

L-Glutathione is a tripeptide (γ-glutamyl-cysteinyl-glycine) that serves as the cell’s master redox buffer, principal ROS/RNS scavenger, and detoxification cofactor. Via glutathione peroxidases (GPx) and glutathione S-transferases (GSTs) it reduces lipid peroxides and conjugates xenobiotics; glutathione reductase (GR) recycles oxidized GSSG back to GSH using NADPH. GSH also modulates signaling through S-glutathionylation, shapes mitochondrial function, and underpins immune and skin pigment biology. Orally, it is sold as a dietary supplement; IV/IM use exists in some regions but is not broadly approved for disease treatment.

Additional Benefits of L-Glutathione Repletion Now Under Investigation

2. Molecular Mechanism of Action

2.1 Core pharmacodynamics

• Antioxidant enzyme substrate: GPx uses GSH to reduce peroxides → GSSG, then GR + NADPH regenerate GSH.

• Detoxification: GSTs conjugate GSH to electrophiles (drugs, pollutants), enhancing solubility/excretion.

• Redox signaling: Protein S-glutathionylation regulates NF-κB, Keap1-Nrf2, and mitochondrial proteins.

• Cysteine reservoir: Maintains intracellular cysteine and supports thiol-disulfide balance.

2.2 Down-stream biology

3. Pharmacokinetics

• Oral GSH (reduced form): Historically thought to be degraded by γ-glutamyltransferase in gut; newer data show dose-dependent plasma/tissue GSH rises with sustained dosing, especially with liposomal or sublingualforms.

• Precursors: N-acetylcysteine (NAC) and glycine (sometimes with glutamine) reliably increase intracellular GSH via γ-glutamyl cycle; GlyNAC shows robust effects in older adults.

• Parenteral: IV GSH yields transient high plasma levels; intracellular uptake depends on breakdown/transport—used off-label in some regions (e.g., dermatology), not broadly approved.

• Distribution: Highest in liver, then erythrocytes, kidney, lung; mitochondrial GSH sustained by dedicated transporters.

• Elimination: Renal excretion of metabolites (cysteinylglycine, cysteine, mercapturates).

4. Pre-clinical and Translational Evidence

4.1 Redox & inflammation

Consistent improvements in oxidative biomarkers and cytokine profiles across stress states (aging, diabetes, pollution exposure), especially with precursor strategies.

4.2 Hepatic/metabolic

Small randomized trials: ALT/AST, hepatic fat (MRI-PDFF) and insulin sensitivity improve modestly; effect size increases when baseline GSH is low.

4.3 Dermatology

Oral/topical studies show mild skin-lightening (one–two shade shifts) over 8–12 weeks; maintenance is required. IV protocols can produce faster effects but raise safety and regulatory concerns.

Evidence quality note: Strong biological plausibility and biomarker improvements; clinical outcomeeffects vary, and many studies are small/short. Precursors (e.g., NAC, GlyNAC) currently have more reproducible human data than high-dose oral GSH alone.

5. Emerging Clinical Interests

6. Safety and Tolerability

• Oral GSH: Generally well tolerated. GI upset, bloating, or cramps at high doses (≥1–2 g/day).

• Inhaled/nebulized: Can induce bronchospasm in reactive airways (sulfur odor); use caution in asthma.

• IV GSH (off-label): Rapid infusion can cause flushing, dizziness, nausea; aseptic technique and qualified supervision are essential; long-term safety data are limited.

• Dermatology: Rare rash or contact sensitivity to topical forms.

• Interactions: May affect chemotherapy redox dynamics; coordinate with oncology. NAC/GSH can alter some lab assays (e.g., creatinine methods).

• Pregnancy/lactation: Food-level exposure is normal; high-dose supplemental/IV use lacks robust data—avoid outside medical indication.

Comparative safety matrix

7. Regulatory Landscape

• Dietary supplement status for oral forms in many countries; no FDA/EMA approval for treating disease.

• IV formulations are not approved for cosmetic indications in many jurisdictions; regulations differ by country.

• Dermatology/cosmetics: Topical GSH is used in OTC products with appearance claims only.

8. Practical Use & Future Directions

• Who benefits most: Individuals with oxidative stress or low baseline GSH (aging, metabolic syndrome, pollution exposure) and those needing detox support; for pigment goals, set modest expectations and emphasize photoprotection.

• Dosing (typical research/supplement ranges):

  • Oral GSH: 250–1,000 mg/day, divided; liposomal/sublingual at the lower end often used.

  • Precursors: NAC 600–1,200 mg/day; GlyNAC protocols supply glycine 1.5–3 g/day + NAC 600–1,200 mg/day.

  • Duration: 8–12 weeks minimum for measurable changes.

• Stacking: Combine with vitamin C/E, selenium (GPx cofactor), alpha-lipoic acid, exercise, and sleep to reinforce endogenous GSH cycling.

• Monitoring: Consider GSH/GSSG ratio, 8-iso-PGF₂α, MDA, ALT/AST, and HOMA-IR in research settings.

• Research needs: Large RCTs comparing oral GSH vs GlyNAC, head-to-head liposomal vs standard, validated clinical endpoints (not just biomarkers), and standardized skin-lightening measures with long-term safety.

Selected References

• Free Radical Biology & Medicine; Redox Biology — Glutathione metabolism, redox signaling, and clinical biomarker changes.

• Hepatology; Liver International — GSH/precursor effects in NAFLD/MASH and liver enzymes.

• Immunity; Journal of Clinical Investigation — Immunological roles of GSH and infection responses.

• Journal of Physiology; Neurobiology of Disease — Mitochondrial GSH and bioenergetics in muscle/neurons.

• Journal of Dermatological Science; Clinical, Cosmetic & Investigational Dermatology — Skin-lightening trials and tyrosinase/UV photobiology.

• Medicine & Science in Sports & Exercise; European Journal of Applied Physiology — Exercise oxidative stress and performance endpoints.

• Thorax; American Journal of Respiratory and Critical Care Medicine — Airway glutathione biology and inhaled/precursor studies.

• Annals of Neurology; Movement Disorders — Brain GSH imaging and pilot therapeutic studies.

• Diabetes Care; Metabolism — Redox, inflammation, and insulin sensitivity under GSH repletion/precursor use.